Genetics

After four years, it took a geneticist a few hours to unravel a boy’s puzzling illness

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From the moment the boy was born on a muggy Texas afternoon in May 2012, his parents, doctors, and nurses knew something wasn’t quite right. From the size of his head to the way he held his body, he wasn’t normal – but it wasn’t clear exactly why.

The parents noticed how tightly their baby clenched his arms and legs to his body. His head was big, and although his limbs were extremely flexible, his neck was stiff. Most worrisome of all, the child was so easily startled, doctors were concerned he was having seizures.

He spent his first five days being poked and prodded in the hospital, and although tests showed he wasn’t having seizures, a fleet of specialists came no closer to a diagnosis. Still, the baby was sent home, a pamphlet about seeing specialist in child development tucked into his discharge paperwork.

His parents — who agreed to discuss their son’s case only if their names weren’t used — hoped the signs that he was different would melt away over time. After all, the pregnancy had been totally normal, with no warning that anything was amiss. But their uncertainty grew as it became clear their boy wasn’t moving or communicating like other babies. No one knew why.

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“From day one,” his mother told STAT, her son “has been a question mark.”

It was nearly four frustrating years before the family got an answer. In the end, all it took was a genetic test and a few hours of a doctor’s online sleuthing.

No answers in sight

During his first years of life, the boy saw a laundry list of specialists. He suffered from heartburn and had breathing problems because of a floppy windpipe, known as laryngomalacia. He held his head at an angle because he had torticollis, or an abnormally tight muscle in the neck.

But those weren’t the only obstacles he faced. He walked and talked late, not sitting on his own until he was a year old – a milestone babies typically hit around six months – and finally starting to coo almost a year-and-a-half late.

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He underwent intense therapy, and by the time he was three years old, he could communicate using signs and pictures; leg braces helped him stand. Yet even as the boy persevered, rising to every challenge and working harder than other kids to reach every milestone, a question gnawed at the family: Why?

That’s where Dr. Daryl Scott, a genetics specialist at Baylor College of Medicine in Houston, came in.

All in a day’s work

It was a sunny mid-March morning in 2016, and Scott was preparing for clinic. He’d risen with the sun and rolled into the office around 6:30 a.m., as he usually did when seeing patients. Scott scanned his schedule, noting that a three-and-a-half-years-old boy was on his list. Scott clicked open the toddler’s chart.

He looked over the findings described in prior doctors’ notes. The symptoms were remarkable, but they didn’t fit together into a known disease or syndrome, Scott thought to himself.

Scott saw that another doctor had sent a sample of the child’s blood for genetic analysis. The test showed that there was a chunk missing of the toddler’s X chromosome. But this abnormality – called Xp11.22 – wasn’t linked to a known genetic disorder, so it had been dismissed as unrelated to his symptoms.

There were two possibilities, Scott mused: The missing part of the gene could be an innocent bystander unrelated to his symptoms – or it could be the cause of a genetic disease that had never before been described.

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Intrigued, Scott delved deeper. He found that the missing stretch of chromosome was normally populated by an alphabet soup of genes: ENPVL1, CENPVL2, MAGED1, and GSPT2. Did lacking these genes have any effect on the animals in which they’d been studied?

Typing away on his computer, Scott scanned a database that linked genetic abnormalities in mice to the symptoms the animals displayed. Interestingly, mice that shared one of the boy’s deletions had learning problems. That caught Scott’s attention.

He investigated further, pulling up a different database containing the genome sequences of 50,000 normal people. If his young patient’s mutation was occasionally present in the genetic code of a person without signs of disease, Scott reasoned, it would indicate the deletion did not cause symptoms. Yet not a single person in this database shared the boy’s deletion, Scott found. And when he searched prior studies, he found that this particular genetic change would indeed be highly likely to cause tangible effects.

Scott’s next question was whether there were other people with the boy’s genetics or symptoms. He turned to a worldwide list of patients with genetic problems not yet linked to a specific disease. It turned out that two siblings – both boys – in the United Kingdom had the same abnormality.

But did they share Thomas’s symptoms? That information wasn’t listed. So Scott shot an email to the U.K. patients’ doctor. Then he closed his laptop and walked into the exam room to meet his patient.

“I went to clinic not knowing what I would find,” he said.

Scott’s examination showed what other clinicians had noticed, including weak muscles, a head large for the child’s body size, and lagging communications skills. He also noted the boy was extremely flexible.

Primed by his morning’s research, Scott mentioned to the mother that he might’ve found the root of these puzzling symptoms.

Nothing was certain, however, until Scott received a response from the U.K. doctor later that afternoon. The message described the two young patients’ symptoms, from low muscle tone to delays in development. They were identical to his own patient’s. He also soon heard from yet another doctor – this one in Dallas – with a patient with the same chromosome deletion and trouble holding a pencil “because his fingers were so bendy,” Scott said.

Scott was ecstatic, about the diagnosis but also about the striking serendipity: In less than a day, he’d confirmed that four patients from three families had a never-before-diagnosed genetic disorder.

He emailed his patient’s mother to share the news. Her world stood still when she saw it pop into her inbox and read the subject line: “We may have found the cause of E’s problems.”

“That question mark dissolved,” she said. “I felt like I wasn’t alone anymore.”

A chance to look to the future

Today, her son is five, he walks on his own, and his speech is improving by leaps and bounds. His syndrome doesn’t yet have a name, and although there’s no cure, knowing what makes him different offers comfort. It’s allowed his family to focus on helping him move forward.

“Everything that he has conquered is such a victory,” his mother said. “I feel so thankful, now that I can look at it from a different perspective, for all he has gone through – for all that we have overcome together.”

Knowing which genes are at play is also important for future planning. The genetic deletion in Scott’s patient, as in the other three children, came from the boy’s mother, who carries the gene but has no symptoms. Women have two X chromosomes, so a gap in one isn’t a problem because the other can take over.

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But should she have another son, he could have the disorder, and future daughters could carry it. By a roll of the dice, her second son – who was already about four months old when her oldest was diagnosed – did not inherit the deletion.

For Scott, the chance to help Thomas and his family has been incredibly rewarding. Experts in genetics may identify a new disease just once every few years, he said, and that process may take months or even years. Being able to come back with an answer in just one day was a thrill – but watching his patient grow has been the greatest reward of all.

“We like finding answers for families,” Scott said. “That’s why we do what we do.”

If you have dealt with a diagnostic puzzle, either as a caregiver or a patient, please email Allison at allisonbondmd@gmail.com.